POS0517 IgA ACPA ARE ASSOCIATED WITH PROGRESSION TO RHEUMATOID ARTHRITIS IN INDIVIDUALS AT-RISK AND DECLINE IN LEVELS AROUND THE DISEASE ONSET
Authors: M. V. Sokolova, F. Hartmann, D. Sieghart, G. Steiner, A. Kleyer, G. Schett, U. Steffen (Née Harre)
Journal: Annals of the Rheumatic Diseases (2022)

Background Anti-citrullinated protein antibodies (ACPA) can precede the diagnosis of rheumatoid arthritis (RA) up to a decade. However, while some ACPA-positive individuals rapidly develop the disease, a considerable proportion are not progressing to RA, and the events triggering the disease outbreak are still poorly understood. While a lot is known about ACPA of IgG class, the role of IgA ACPA is still not defined. Objectives We aimed to look into IgA ACPA isotypes in individuals at-risk for RA and their role in RA development. Methods IgA1 and IgA2 ACPA were measured cross-sectionally in 30 seropositive (IgG ACPA-positive) RA patients, 29 seronegative RA patients, 63 individuals at-risk for RA (positive for IgG ACPA and/or anti-modified citrullinated vimentin antibodies and with joint complaints) and 32 healthy controls. In addition, IgA ACPA levels were compared in 24 RA at-risk individuals who developed RA during a follow-up of 14 months and in 21 individuals who did not. Furthermore, longitudinal measurements of IgA1 and IgA2 ACPA levels 1-28 months prior to, at and 1-18 months after the onset of RA were performed in 14 at-risk individuals and in 9 individuals from a confirmation retrospective cohort of RA patients from the Medical University of Vienna. Cut-offs were set based on the comparison of IgA ACPA levels in RA patients versus healthy controls. Rather than prioritizing specificity, as is done for diagnostic tests, we aimed to define reliably detectable amounts of IgA ACPA, with both sensitivity and specificity not under 70% – 3 µg/ml for total IgA ACPA; 2.46 µg/ml for IgA1 and 0.6 µg/ml for IgA2 ACPA. Results Serum levels of both IgA ACPA subclasses were elevated in individuals at-risk, with no significant difference to patients with established IgG ACPA-positive RA. Interestingly, 41.4% of IgG ACPA-negative patients had detectable amounts of IgA ACPA. IgA1 ACPA, but not IgA2 ACPA levels were higher in individuals at-risk who developed RA in the next 14 months than in those who did not (4.54 vs. 2.05 µg/mL, p=0.03); and the percentage of those developing RA was higher in IgA1 ACPA-positive at-risk individuals (64.3% versus 35.3%). Interestingly, during the transition to RA, in the majority of IgA ACPA-positive individuals a decline in IgA1 ACPA levels at the time of RA diagnosis (-26%; p=0.085), as well as in the first months after the RA diagnosis (-38%; p=0.0002) was observed. This observation was confirmed in an independent cohort. IgA2 ACPA declined only after the diagnosis (33%; 10-64%; p=0.0237), and no significant change was observed for IgG ACPA. Conclusion Both IgA ACPA subclasses were elevated in individuals at-risk for RA. Positivity for IgA1 ACPA was associated with the progression to RA in the next 14 months. IgA1 ACPA levels declined in the months preceding the diagnosis of RA and in the months after the diagnosis, which might reflect pathophysiological events happening at the time of the disease outbreak. Acknowledgements We thank Holger Bank from Orgentec Deiagnostika, Mainz for the supply of CCP-coated plates. Disclosure of Interests Maria V Sokolova: None declared, Fabian Hartmann: None declared, Daniela Sieghart: None declared, Günter Steiner: None declared, Arnd Kleyer Speakers bureau: Novartis, Lilly, Consultant of: Lilly, Gilead, Novartis,Abbvie, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Ulrike Steffen (née Harre): None declared.